Preclinical Cushing's syndrome resulting from black adrenal adenoma. A case report.

A 59-year-old Japanese woman, admitted for the treatment of diabetes mellitus and hypertension, was incidentally discovered to have a solid mass of 1.4 cm in diameter by CT scan with the attenuation value of 38 Hounsfield units, relatively higher for ordinary adrenal adenomas. Magnetic resonance imaging revealed no reduction of signal intensity on opposite-phase image on T1-weighted sequence. Adrenal scintigraphy imaging with 131I-adosterol did not show any uptake of the isotope in the area corresponding to both adrenals. Although she had no characteristic feature of overt Cushing's syndrome, her serum cortisol level was not suppressed after an overnight dexamethasone administration. She was diagnosed as having preclinical Cushing's syndrome. Left adrenalectomy was performed, revealing the well-circumscribed black tumor, mainly consisted of compact cell, in which cytoplasm was filled with numerous granules pigmented with dark to golden brown colors on hematoxylin-eosin staining. These findings suggested that her incidentaloma was a black adrenal adenoma. Production of steroid hormones was confirmed by immunohistochemical analysis of steroidogenic enzymes and by measurement of the tissue contents of hormones, whose levels were comparable with those in adenomas of overt Cushing's syndrome. This is the first case report of preclinical Cushing's syndrome resulting from black adrenal adenoma.

Virilising adrenocortical tumours in children.

UNLABELLED: Adrenocortical tumours (ACT) are a rare but important cause of virilisation in infancy and childhood. Four cases of virilising ACT are presented. Two girls (age 0.9 years and 3.9 years) and two boys (age 6.2 years and 6.4 years) had symptoms and signs of virilisation before the age of 6 years. Diagnosis of a virilising adrenal tumour was confirmed by laboratory tests, diagnostic imaging and histology. However, one female patient was misdiagnosed and treated for 3 months as atypical congenital adrenal hyperplasia. Ultrasonography of the adrenal region could not visualise the tumour in three out of four cases. The most sensitive method of diagnostic imaging was MRI. In all cases, treatment consisted of complete surgical resection of the adrenal tumour by open abdominal surgery. Immunohistochemistry was performed in all patients and in two patients there was an overexpression of p53, indicating p53 mutation and in three cases the ki67 proliferation index was greater than 5%. The classification of ACT in childhood is extremely difficult. Histology scores adapted from adrenal tumours in adults and molecular markers are under investigation, but there is still not enough clinical experience since ACT are so rare. CONCLUSION: Long-term follow-up is mandatory not only because of the uncertainty in classification of adrenocortical tumours, but also for observation of growth and pubertal development.

The biochemical study of intermaxillary fixation (IMF) stress in oral surgery inpatients.

Although intermaxillary fixation (IMF) is performed to treat the patients with maxillary fracture, this procedure is very stressful to the patients. IMF has been reported to increase noradrenaline (NA) release in the brain and elevate plasma corticosterone contents in the rat. These changes were significantly attenuated by diazepam, an anxiolytic of the benzodiazepine family. These results suggest that IMF could greatly affect the pituitary-adrenal system as a stress. In the present study, in order to examine the influence of IMF on the human body function, we measured levels of 17-hydrocorticosteroids (17-OHCS) and 17-ketosteroid (17-KS), which are metabolites of the adreno-cortical hormone cortisol, in the urine of inpatients undergoing IMF. The subjects were requested to fill out a questionnaire on irritableness caused by IMF. In these patients, urinary 17-OHCS levels were significantly increased after IMF and well correlated to the results of the questionnaire. The finding suggested that urinary 17-OHCS levels reflect stress related to IMF, and that such stress mainly causes an irritated feeling. Natural killer cell activity (NK activity), which is considered to be related to stress, was measured in these patients. The relationship between 17-OHCS levels and NK activity was examined in reference to the results of the questionnaire. Questionnaire showed that most patients noted insomnia and an irritated feeling during IMF. To examine the influence of anxiolytic agents on stress related to IMF, an anxiolytic agent, ethyl loflazepate, was administered during IMF, and urinary 17-OHCS levels were measured. There was no correlation between 17-OHCS levels and NK activity in the patients. Furthermore, no correlation was observed between visual analogue scale (VSA) and NK activity. Increases in 17-OHCS levels in the group treated with ethyl loflazepate, an anxiolytic of the benzodiazepine family, were significantly lower than in the untreated group. This suggests that ethyl loflazepate reduced stress responses to IMF. It has been reported that NK activity is reduced inpatients with depression or chronic fatigue syndrome. However, NK activity may not be affected by mechanical stress such as IMF. The finding that an anxiolytic agent, ethyl loflazepate, inhibited stress responses to IMF further suggests that anxiolytic drugs are very useful for treatment of irritated feeling of the patients undergoing IMF.

[Cushing syndrome--a pathologic analysis based on 216 resected specimens].

OBJECTIVE: To study the morphological features of adrenal cortex in Cushing's syndrome and the correlation of morphological changes with clinical manifestations. METHODS: 216 cases of Cushing's syndrome were collected. Among these there were 160 cases of adrenal hyperplasia, 50 cases of adenoma and 6 cases of adenocarcinoma of adrenal cortex. The morphometric method was used to measure the thickness of adrenal cortex microscopically. The weight of the resected specimens were carefully recorded and correlated with clinical laboratory findings and clinical manifestations. RESULTS: In adrenal cortex hyperplasia, the thickness and weight of the adrenal cortex increased gradually in the order of mild, moderate and severe hyperplasia. The hyperplasia and hypertrophy of the compact cell are very common in these specimens. The frequency of compact cell predominant cases was also increased in severe hyperplasia. The weight and size of the tumor differed significantly between adenoma and adenocarcinoma of the adrenal cortex. CONCLUSION: In Cushing's syndrome, adrenal cortex hyperplasia is the most common. The grade of hyperplasia was well correlated with clinical laboratory findings. Increase of frequency of compact cell predominance is important morphological feature of hyperplasia of adrenal cortex. Adenoma should be considered when atrophy of adjacent cortex is present. The tumor size and weight as well as mitosis are important parameters in differential diagnosis between adenoma and adenocarcinoma of the adrenal cortex, but the infiltration of capsule and blood vessels and/or metastasis still remain the gold criteria for diagnosis of adrenal adenocarcinoma.

[Diagnosis, surgical treatment and prognosis in endocrine hypertension of adrenal origin]. / Diagnostika, khirurgicheskoe lechenie i prognoz pri endokrinnykh gipertoniiakh nadpochechnikovogo geneza.

162 patients with adrenal hypertension have been examined. 48 of them had Cushing's syndrome, 10--aldosteromas, 85 --icenko--Cushing disease. The examination of patients with endocrine hypertension included hormonal background study, computer and MR tomography thin-needle biopsy and made it possible to make valid clinical and topical diagnosis in all cases. Magnetic-resonance tomography appeared to be the most efficient diagnostic method in the syndrome of hypercorticoidism. Ultrasound examination is the most available and highly informative method of revealing hormonally active adrenal tumors when they are more than 1 cm in size. An adequate preoperative preparation equally with an optimal scope of surgery and efficient postoperative substitution hormonal therapy are key factors in treatment of endocrine adrenal hypertension.

Studies on circadian periodicity of plasma 17-hydroxycorticosteroids (17-OHCS) in carcinoma of the breast.

Circadian periodicity of plasma 17-hydroxycorticosteroids (17-OHCS) was studied in 25 histopathologically proved breast cancer patients pre operatively and on the 9th postoperative day and in 15 healthy women under tropical conditions. A marked rhythm in plasma 17-OHCS concentration was noticed in healthy controls. The maximal concentration occurred at 06:00 followed by a consistent decline throughout the daytime, reaching a minimum at 00:00 with an amplitude statistically significantly different from zero and an acrophase around 08:56. The plasma 17-OHCS concentration was found to be elevated at all sampling hours in breast cancer patients, irrespective of the stage of the disease. However, the degree of elevation and disruption of rhythm was more pronounced in advanced sages, preoperatively, in comparison to other groups. Moreover, the values declined markedly at all collection hours after mastectomy, approaching usual values and rhythm characteristics on the 9th postoperative day.

Familial adrenocorticotropin-independent Cushing's syndrome with bilateral macronodular adrenal hyperplasia.

Familial Cushing's syndrome is rare, and when it occurs, it is usually associated with primary micronodular dysplasia. We report two cases, a mother and daughter, who each presented with clinical features of Cushing's syndrome at age 38 yr and were found to have ACTH-independent macronodular adrenal hyperplasia. In each case, bilateral adrenalectomy revealed the massively thickened adrenal cortex with nodules up to 1.3 cm in diameter and hyperplasia between nodules. Dynamic testing showed no suppression of free cortisol with high dose dexamethasone and no stimulation of 17-hydroxycorticosteroids with metyrapone. Two samples of serum obtained preoperatively from one patient that showed ACTH immunoreactivity of 4.6 and less than 2.2 pmol/L, respectively, each showed less than 2.2 pmol/L ACTH bioactivity. The lack of suppression with high dose dexamethasone, lack of stimulation with metyrapone, and low levels of ACTH immunoreactivity and bioactivity suggest that the bilateral hyperplasia was not dependent upon ACTH. These patients represent the first cases of ACTH-independent macronodular adrenal hyperplasia occurring in two generations of one family and illustrate the expanding clinical spectrum of Cushing's syndrome.

[Psycho-electroregulation in conservative treatment of patients with uterine myoma]. / Psikhoélektroreguliatsiia v konservativnoi terapii bol'nykh miomoi matki.

Basing on the concept of the uterine myoma presenting as a psychosomatic process that manifests in ischemic disease of the uterus, the author has tried psychoelectrostimulation in 76 patients with interstitial and subserous interstitial myomas as a method of psychotherapy and electrotranquilization. Indications for such treatment are the presence of psychoemotional stress syndrome (high anxiety level, pain and hemorrhagic syndromes, dysuria) and a rapid growth of the tumor. The reference group consisted of 73 patients with the same myoma forms, treated by hormonal therapy. Psychoelectroregulation has exerted a regulating effect on the central nervous, cardiovascular, endocrine and reproductive systems, it eliminated or alleviated the neurotic symptoms, and slowed down or arrested the tumor growth.

[Endocrine and ultrasound examination of hirsutism]. / Endokrinologische und ultrasonografische Untersuchung des Hirsutismus.

One hundred and fourteen nontumorous hirsute women were investigated. The degree of hirsutism, the menstrual abnormalities and the level of 17-ketosteroids, of DHEA, of 17-OH-corticoids in urine and RIA of total and free testosterone and of sex binding globulins (SHBG) in blood were performed. On the basis of endocrinological and ultrasonographic determinations 3 patients were diagnosed as congenital adrenal hyperplasia, 35 patients as late onset adrenal hyperplasia and 57 women as polycystic ovary syndrome (PCO). The maximal mean level (X + SD) of total and free testosterone above 0.5 ng/ml relatively above 5.05 pg/ml were performed in 94.3% relatively 97.1% in late onset adrenal hyperplasia and in 78.9% relatively 87.7% in PCO. The diagnosis of PCO is possible among 75% of all hirsute patients after exclusion the patients with late onset adrenal hyperplasia. The PCO is confirmed by hormonal or/and ultrasonographic examination. The diagnosis of late onset adrenal hyperplasia is allowable only by hormonal investigation.

Continuous adrenocorticotropin administration in hypopituitarism produces asynchronous increases of deoxycorticosterone and 11-deoxycortisol relative to other reduced zona fasciculata steroids.

Short term suppression of ACTH by dexamethasone effects limited reduction in plasma deoxycorticosterone (DOC) while cortisol levels are almost completely suppressed in normal control subjects. The zona fasciculata (ZF) microsomal cytochrome P-450(21) appeared less influenced by lack of ACTH than mitochondrial cytochrome P-450(11 beta-18). Eleven patients with hypopituitarism were studied to quantitate basal ZF microsomal and mitochondrial derived steroids and their acute and extended responses to ACTH. Basal levels of 11-deoxycortisol (S) and DOC were modestly reduced (70% and 53%, respectively), while other ZF steroids were almost completely absent. Acute and prolonged ACTH treatment amplified the discrepancy in both plasma levels and production rates. DOC and S demonstrated prompt and sustained increases similar to those in normal controls, while cortisol, 18-hydroxydeoxycorticosterone, and corticosterone showed a slow subnormal recovery of steroid production. The preservation of microsomal cytochrome P-450(21) and P-450(17 alpha) to maintain DOC and S levels contrasts the reduced and delayed responses of steroids dependent on mitochondrial cytochrome P-450(11 beta-18), cortisol, corticosterone, and 18-hydroxydeoxycorticosterone. A greater effect of ACTH deficiency on mitochondrial over microsomal cytochrome P-450 activity is demonstrated, and in addition, the possibility is raised that other non-ACTH regulators sustain microsomal cytochrome P-450(21) and P-450(17 alpha) in a setting of reduced ACTH-stimulated factors.

Plasma levels of ovarian steroids, including 17 alpha,21-dihydroxy-4-pregnene-3,20-dione and 3 alpha,17 alpha,21-trihydroxy-5 beta-pregnan-20-one, in female plaice (Pleuronectes platessa) induced to mature with human chorionic gonadotrophin.

In one previous paper we reported on the identification of 11-deoxycortisol and 3 alpha,17 alpha,21-trihydroxy-5 beta-pregnan-20-one in the ovaries and plasma of mature female plaice and also described the development of radioimmunoassays for these two steroids. The present paper describes temporal changes in plasma levels of the free and conjugated forms of these and of some other steroids (17 alpha,20 beta-dihydroxy-4-pregnen-3-one, 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one, 17 alpha,20 alpha-dihydroxy-4-pregnen-3-one, 17 alpha-hydroxy-4-pregnen-3-one, testosterone, and 17 beta-oestradiol) in female plaice injected with and without human chorionic gonadotrophin (HCG). Oocyte final maturation, but not ovulation, was induced by HCG injections. Levels of most of the steroids were also elevated by the HCG injections and were significantly higher than in control fish throughout the experiment (112 hr). The two most abundant steroids were 11-deoxycortisol and 3 alpha,17 alpha,21-trihydroxy-5 beta-pregnan-20-one (up to 600 ng ml-1). Only relatively small amounts of 17 alpha-hydroxy-4-pregnen-3,20-dione (less than 15 ng ml-1), 17 alpha,20 beta-dihydroxy-4-pregnen-3-one, and 17 alpha,20 alpha-dihydroxy-4-pregnen-3-one (less than 5 ng ml-1) were found. 17 alpha,20 beta,21-Trihydroxy-4-pregnen-3-one was not present. Testosterone and 17 beta-oestradiol levels rose briefly, in response to the first of the two HCG injections, and then fell significantly. The ratio of conjugated to free steroids (except for 17 alpha-hydroxy-4-pregnene-3,20-dione and 17 beta-oestradiol) was almost always greater than 1. In the HCG-injected fish, there was a significant negative correlation between the response of 17 beta-oestradiol levels and the response of 11-deoxycortisol and 3 alpha,17 alpha,21-trihydroxy-5 beta-pregnan-20-one levels. This further confirms that, as teleosts approach the time of full maturity, there is switch-over in the ovaries from predominantly C19 and C18 steroid production to predominantly C21 steroid production.

Decreased melatonin concentration in Cushing's syndrome.

To determine the effect of hypercortisolaemia on the melatonin circadian secretion 12 patients with pituitary or adrenal dependent Cushing's syndrome and 5 healthy controls were studied. The melatonin circadian rhythm of secretion, observed in the control group, was abolished in the patients with hypercortisolaemia. Mean nocturnal melatonin levels and the integrated 24-hour secretion were significantly lower in the patients studied than those of the controls. Thus, in patients with Cushing's syndrome the melatonin levels are decreased and the circadian rhythm of this hormone is abolished.

[A case of the benign adrenal adenoma with remarkably high concentrations of deoxycorticosterone and 11-deoxycortisol].

The case was a 33-year-old woman with hypertension and hypokalemia, who presented depression of renin activity and the abnormal elevation of plasma deoxycorticosterone (DOC) and 11-deoxycortisol on laboratory tests. After admission, abdominal CT scan, 131I-adosterol scintigram and adrenal venogram revealed a tumor in the left adrenal, which histologically seemed to be benign. When the tumor was resected, blood pressure and all the biochemical data returned to normal range. DOC and 11-deoxycortisol levels in the tumor were abnormally elevated as compared with those in the normal adrenal tissue. These findings suggested that the abnormal elevation of hormone levels resulted from depression of 11 beta-hydroxylase. Though numerous adrenal tumors have been documented, we rarely encounter an apparently benign adrenal tumor that produces 2 kinds of hormones. This seemed to be the first case of benign adrenal tumor in which both DOC and 11-deoxycortisol were elevated.

Resistance to bromocriptine in prolactinomas.

Bromocriptine therapy normalizes PRL secretion in most, but not all, patients with prolactinomas. This study was undertaken to determine the mechanism(s) responsible for bromocriptine resistance in patients with a PRL-secreting macroadenomas (n = 5) or microadenomas (n = 3). Their mean basal plasma PRL value was 807 +/- 220 (+/- SE) micrograms/L before treatment, and their nadir mean value was 354 +/- 129 micrograms/L during chronic therapy with 15-30 mg bromocriptine daily; four of the eight patients had an increase in tumor size during therapy. In cultures of prolactinoma cells from patients normally responsive to bromocriptine therapy (n = 10), considered as controls, 10(-9) mol/L bromocriptine inhibited PRL release by 71 +/- 6% (+/- SE), and the half-inhibitory dose was 7 x 10(-11) mol/L. In contrast, in cultures of prolactinoma cells from five patients resistant to bromocriptine, PRL release was inhibited by only 3-42% at 10(-9) mol/L bromocriptine. This partial inhibition was reversed by a 100-fold excess of haloperidol. In contrast, the effects of other inhibitors of PRL release (10(-8) mol/L T3 and 10(-8) mol/L somatostatin) or of a stimulator (10(-8) mol/L angiotensin-II) on cells from resistant and normally responsive patients were similar. In cell membranes from five bromocriptine-responsive adenomas the density of dopaminergic binding sites, labeled by [3H] spiroperidol was 243 +/- 65 (+/- SE) fmol/mg protein. In adenomas from the eight patients resistant to bromocriptine therapy the density of [3H]spiroperidol-binding sites lower (145 +/- 31 fmol/mg protein). In adenomas from five resistant patients whose tumor had grown during therapy the density of binding sites was 25 +/- 3 fmol/mg protein, 10% of that in normally responsive patients. The effects of dopamine on adenylate cyclase activity also were different in the three groups of adenomas. Dopamine inhibited adenylate cyclase activity by 28.8 +/- 5.6% in five bromocriptine-responsive tumors and by 16.5 +/- 4.3% in adenomas from eight resistant patients. In contrast, in the five patients whose tumors grew during therapy dopamine paradoxically stimulated adenylate cyclase activity (+26.4 +/- 9.8%). There was a very good correlation between the density of dopaminergic binding sites and maximal inhibition of adenylate cyclase activity in bromocriptine-responsive prolactinoma patients (r = 0.90) and resistant patients who had no tumor growth during therapy (r = 0.94).(ABSTRACT TRUNCATED AT 400 WORDS)

[Screening for congenital adrenal hyperplasia in Hungary]. / A congenitalis adrenalis hyperplasia célzott szürése Magyarországon.

Measurement of blood-spot 17-hydroxyprogesterone (17-OHP) concentration was used to identify cases of congenital adrenal hyperplasia (CAH) among patients with inappropriate virilization and/or salt wasting. Between 1978 to 1986 61 cases with 21-hydroxylase deficiency among 707 patients (278 newborns, 204 infants and 225 children) were identified. The incidence of classical CAH was calculated for a seven year prospective trial period using the blood-spot 17-OHP method in selective screening. There were 38 salt-losers and 14 simple virilizers in 968,303 live births giving an incidence of 1 in 18,000 for CAH in the Hungarian population. The use of a central laboratory facility to measure the blood-spot 17-OHP concentrations is proposed as a valuable initial method to investigate patients at risk for CAH in countries where blood steroid assays are not readily available in hospitals.

Adrenal cortex hormones in male epileptic patients before and during a 2-year phenytoin treatment.

Serum levels of progesterone, cortisol and phenytoin as well as the excretion of 17-OHCS were determined in 45 male epileptics before and during 24 months of the therapy. A significant decrease of the hormones was found in untreated patients. Phenytoin administration caused further decrease of cortisol and its metabolite 17-OHCS levels and a compensation of progesterone serum concentration.

[The use of a radioimmunologic method of analysis of 11-deoxycortisol for the evaluation of the function of the pituitary-adrenal cortex system during the metopirone test]. / Primenenie radioimmunnogo metoda opredeleniia 11-dezoksikortizola dlia otsenki funktsii sistemy gipofiz-kora nadpochechnikov v usloviiakh metopironovogo testa.

A radioimmunoassay of II-deoxycortisol in human and animal blood plasma was developed. The antiserum used in the method was prepared against a conjugate of II-deoxycortisol-3(0-carboxymethyloxime) and bovine serum albumin. Specificity of the antiserum was determined in cross reactions using 32 steroids. High specificity of the antiserum allowed to determine II-deoxycortisol without preliminary chromatographic isolation. Sensitivity of the method enabled to detect 25 pg of II-deoxycortisol. The intra- and interassay variations were less than 10% and 15%, respectively. The method was used for evaluation of hypophysis-adrenal cortex system functions under the conditions of metopirone test.

Primary aldosteronism by carcinoma of the adrenal cortex.

A 58-year-old white woman with hypertension and severe hypokalemia was found to have a carcinoma of the left adrenal gland. Plasma renin activity was constantly under the normal limit, while plasma aldosterone levels were pathologically elevated. Plasma cortisol (8:00 a.m.) and excretion rates of urinary free cortisol were within the normal range. After an adrenalectomy, relapsing excessive aldosterone secretion was successfully treated with opDDD (Lysodrene). Ten months after the diagnosis was established, the patient died from a bleeding liver metastasis.

Circadian periodicity of plasma 17-hydroxycorticosteroids in advanced breast cancer.

Circadian periodicity of plasma 17-hydroxycorticosteroids (17-OHCS) was studied in ten patients with advanced breast cancer and ten healthy volunteers. A marked rhythm in plasma 17-OHCS concentration was noticed in normal controls; the maximum concentration occurred at 0800 hr followed by a consistent decline throughout the daytime, reaching a minimum at 0000 hr. The circadian rhythm of plasma 17-OHCS was found to be deranged in six of the patients with breast cancer, but a normal rhythmic pattern was seen in the remaining four patients, although the values remained elevated at all time points of the 24-hr cycle in the patients with breast cancer compared to the healthy volunteers. The normal and altered plasma 17-OHCS rhythms in the patients presumably could be due to individual susceptibility and response to the pathophysiological stress of cancer.